HPV-VACCINE. FORSKERENS BLIK PÅ HISTORIEN · HPV-VACCINE. FORSKERENS BLIK PÅ HISTORIEN ! ... -...
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HPV-VACCINE.
FORSKERENS BLIK PÅ
HISTORIEN !
Kåre Mølbak
Statens Serum Institut
1. HPV VACCINE PR FØDSELSKOHORTE, 30. JUNI 2017
Uptake of first HPV-vaccine by year of birth, females, 1993-2005
FORSKERENS PERSPEKTIV
Hvilken forsker ?
- Epidemiologen ?
- Biologen/immunologen ?
- Sociologen ?
- Antropologen ?
- Kommunikationsforskeren ?
- Psykologen ?
- Økonomen ?
Alle kan give relevante bidrag til forskning og til at genoprette tillid.
EPIDEMIOLOGENS BLIK
Velundersøgte vacciner, god effekt på HPV-relateret sygdom, meget sikre
- 100 millioner vaccinerede og givet ca 270 millioner vacciner på verdensplan
- Gode registerbaserede studier styrker vor viden om vaccinen som en sikker
vaccine
Er der symptomer, som endnu ikke er fastslået som bivirkninger til HPV-vaccinen ?
Epidemiologen vil som minimum forvente, at disse ses hyppigere blandt eksponerede
(dvs vaccinerede) end uvaccinerede (ikke-vaccinerede)
- Denne dokumentation foreligger ikke for det ”danske HPV-vaccine syndrom”
Vi ved også:
M edicinsk uafklarede symptomer er i forvejen hyppige blandt unge piger og kvinder
I de relevante fødselsårgange er pigerne næsten alle vaccinerede
Talrige historiske eksempler på sociale ”epidemier”, hvor en årsagssammenhæng
konstrueres socialt
HILLS CRITERIA (1965)
1. Strength: A small association does not mean that there is not a causal effect, though the larger the
association, the more likely that it is causal.
2. Consistency: Consistent findings observed by different persons in different places with different
samples strengthens the likelihood of an effect.
3. Specificity: Causation is likely if there is a very specific population at a specific site and disease with
no other likely explanation. The more specific an association between a factor and an effect is, the
bigger the probability of a causal relationship.
4. Temporality: The effect has to occur after the cause (and if there is an expected delay between the
cause and expected effect, then the effect must occur after that delay).
5. Biological gradient: Greater exposure should generally lead to greater incidence of the effect.
6. Plausibility: A plausible mechanism between cause and effect is helpful.
7. Coherence: Coherence between epidemiological and laboratory findings increases the likelihood of
an effect. However, Hill noted that "... lack of such [laboratory] evidence cannot nullify the
epidemiological effect on associations".
8. Experiment: "Occasionally it is possible to appeal to experimental evidence".
9. Analogy: The effect of similar factors may be considered.
HILLS CRITERIA (1965)
1. Strength: A small association does not mean that there is not a causal effect, though the larger the association, the more likely
that it is causal.
2. Consistency: Consistent findings observed by different persons in different places with different samples strengthens the
likelihood of an effect.
3. Specificity: Causation is likely if there is a very specific population at a specific site and disease with no other likely explanation.
The more specific an association between a factor and an effect is, the bigger the probability of a causal relationship.
4. Temporality: The effect has to occur after the cause (and if there is an expected delay between the cause and expected effect, then the effect must occur after that delay).
5. Biological gradient: Greater exposure should generally lead to greater incidence of the effect.
6. Plausibility: A plausible mechanism between cause and effect is helpful.
7. Coherence: Coherence between epidemiological and laboratory findings increases the likelihood of an effect. However, Hill
noted that "... lack of such [laboratory] evidence cannot nullify the epidemiological effect on associations".
8. Experiment: "Occasionally it is possible to appeal to experimental evidence".[1]
9. Analogy: The effect of similar factors may be considered.
INGEN AF HILL’S KRITERIER ER OPFYLDT
Pigerne havde øget sygelighed før første vaccine:
- Udelukker principielt ikke at der kan være bivirkninger
- Men svækker den mulige hypotese, idet årsag skal komme før
effekten (og med en plausibel latenstid)
- Giver også en opfattelse af en særlig profil ift sundhedssøgende
adfærd for disse kvinder
HVORFOR GIK DET SÅ GALT ?
STORIES VERSUS NUMBERS
Actress Mira Wanting dies of
cervical cancer, 34 years of age, in
2012
Reporting of adverse events: Stimulated by the program “The
Vaccinated Girls” broadcasted 26 March 2015, by TV2
Features interviews with families and vaccinated girls with medically
unexplained symptoms .
11
HVORFOR ER PIGERNE SYGE?
Diagnoser er individuelle
Bivirkninger
- Utvivlsomt for enkelte, men sikkert få.
Body Distress Syndrome ?
- Reaktion på skade/trauma, eksempelvis whiplash
- Symptomer fra det autonome nervesystem, mave-tarmsystem, bevægeapparat
Attribution – den sociale/mentale konstruktion af en årsag
- Sammenfald mellem symptomer og vaccination
Iatrogenicitet
- Artefakt af medicinsk specialisering og dårlig forskning
• Kan fastholdes ved en biologisk tilgang
- ”Blame-X syndromet”: En forhandling om at finde en forklaring…
• Hellere ”bivirkninger” end en vanskelig samtale
• Reducere angsten for det ukendte
HVORDAN KOMMUNIKERES EFFEKTIVT ?
HPV can infect your daughter and seriously harm her health. You can protect her by getting her vaccinated.
GRUND TIL OPTIMISME…
Skift i indhold af mediedækning
- Godt hjulpet af diskursen om fake news
Faldende antal rapporterede bivirkninger
Vaccinationsdækningen er på vej op
Spændende forskning på vej
Forskere og myndigheder kommer ned fra tårnet for at møde de bekymrede mødre
- Vigtigt at være modig og holde fast på kvalitet i forskning
Tak til bl.a.
• Stine Jacobsen og Bolette Søborg, National Health Authority
• Camilla Hiul Suppli, Niels Dalum Hansen, Palle Valentiner-Branth, Tyra Krause,
Morten Frisch og Anders Hviid, SSI
• Line Michan, Danish Medicines Agency
• No conflicts of interest to declare
EXTRA SLIDES
LIDT OM HPV EPIDEMIOLOGI
Danmark:
• 380 tilfælde af livmoderhalskræft
• 120 dødsfald
• 15.000 celleforandringer
• > 5.000 keglesnit
UDVIKLING AF VACCINE MOD HPV
1976: Zur Hausen fremsætter hypotesen at humant
papillomvirus spiller en rolle i udvikling af cervix-cancer
1983: HPV16 og HPV18 forbindes med cervixcancer
- ”en nødvendig årsag”
Udvikling af vaccine starter
- University of Queensland, Australien, patent 1991, på
vaccine like particles (VLP)
2006: Første vaccine, Gardasil (Merck), godkendes
2007: Cervarix (GSK) godkendes
2007: Sundhedsstyrelsen laver en medicinsk
teknologivurdering mhp inklusion i vaccinations programmet
- Anbefaling om at oprette et vaccinationsregister
2008: Gardasil inkluderes i børnevaccinationsprogrammet
(opstartsprogram til børn født i 1993-1995)
2009: Vaccination starter (12 til 15 år gratis vaccination)
Harald zur Hausen,
Nobelpris 2008
TIDSLINJE 2
2012-13: Omfattende catch-up program til kvinder årgang 1985-1992 (op
til 27 år)
2014: To dosis program for de 12-13 årige piger indføres (EPI-NYT 28-
32, 2014)
2014: Gardasil 9 godkendes
- Højrisiko typer 16, 18, 31, 33, 45, 52 og 58
- Lavrisiko typer 6 og 11
1. februar 2016: Danmark beslutter at skifte fra Gardasil til Cervarix pga
udfald af et lovpligtigt udbud (se EPI-NYT 2/2016)
Nu: Nyt udbud – går efter Gardasil 9
FAKTA OM VACCINERNE
Alle tre vacciner har høj effektivitet over for HPV-infektion
- Blandt ikke inficerede
Høj sygdomsbyrde af HPV relateret sygdom
- Cervixcancer, men også anal, penis, vulva & vagina
- Mundsvælget
- Kondylomer
Velundersøgte vacciner, god effekt, sikre
- 100 millioner vaccinerede (ca 270 millioner personer) givet på
verdensplan
Langvarig beskyttelse
- Også efter blot to doser
Faldende priser
- Vigtigt i globalt perspektiv – vi har et ansvar
Baldur-Erikson et al,
Cancer Causes Control 2014
CIN
2 +
Totale befolkning
Screenede
© Copyright 2016 American Sexually Transmitted Diseases Association. Published by Lippincott Williams & Wilkins, Inc.
2
Dramatic decline in the incidence of genital warts
Significant Reduction in the Incidence of Genital Warts in Young Men 5 Years Into the Danish Human Papillomavirus Vaccination Program for Girls and Women.Bollerup, Signe; Baldur-Felskov, Birgitte; MD, PhD; Blomberg, Maria; MD, PhD; Baandrup, Louise; MD, PhD; Dehlendorff, Christian; Kjaer, Susanne; MD, MDSc
Sexually Transmitted Diseases. 43(4):238-242, April 2016.DOI: 10.1097/OLQ.0000000000000418
FIGURE 1 . Half-yearly IRs of GWs per 100,000 person-years in Denmark between 2006 and 2013, stratified by sex and age.
CARE-SEEKING BEFORE FIRST VACCINE
Case-control study
Cases: 361 females with severe adverse reactions reported to DMA
Controls: 163.910 matched on municipality, age, year of first HPV vaccine
- Females
- Vaccinated
- No reports of adverse reactions
AGE DISTRIBUTION (CASES)
The bimodal distributions reflects the
catch-up programme
Table 3. Final multivariable model showing health care-seeking in the two years prior to
vaccination in 316 Danish females who reported suspected adverse events to HPV vaccination
compared with 163,910 matched controls.
Mølbak K, Hansen ND, Valentiner-Branth P (2016) Pre-Vaccination Care-Seeking in Females Reporting Severe Adverse Reactions
to HPV Vaccine. A Registry Based Case-Control Study. PLoS ONE 11(9): e0162520. doi:10.1371/journal.pone.0162520
http://journals.plos.org/plosone/article?id=info:doi/10.1371/journal.pone.0162520
THE REPORTING OF SUSPECTED
ADVERSE EVENTS AND THE RESULTING
CONCERNS ABOUT VACCINE SAFETY
”THE DANISH SIGNAL”
From 2013: Danish Medicines Agency received an increasing number of
reports of suspected adverse events (AE)
- 2320 adverse events 2009-2016, of which 1023 were classified as
severe
• Persistent or significant incapacity
- Only 10% of the 488 reports received in 2015 had onset in 2015
Source: Danish Medicines Agency
IN RELATION TO THE YEAR OF THE ONSET
0
20
40
60
80
100
120
140
160
2009 2010 2011 2012 2013 2014 2015
Reported adverse events per 100,000 vaccines soldSource: Danish Medicines Agency
THE CLINICAL PICTURE
Medically unexplained physical symptoms
- Symptoms from the nervous systems (”autonomic dysfunctions”)
• Including dizziness, syncope, weakness, headache, disordered sleep
- Fatigue
- Pain
- Musculoskeletal symptoms
Some recieved the diagnosis POTS – postural orthostatic tachycardia syndrome
- 60-degree head-up tilt table
- Orthostatic intolerance and a sustained heart rate increment according to
defined criteria
Chronic fatigue syndrome
Complex regional pain syndrome
From Brinth L et al, Dan Med J
2015
53 patients seen at one centre
Considerable overlap in
symptoms between POTS and
Chronic Fatigue
Syndrome/Myalgic
Encephalomyelitis (CFS/ME)